June 22, 2008

How to ruin your credibility

The recent post at Terra Sigliata brought up memories of my first thesis project in Prague. I got involved with ‘independent cancer researchers’ and one of them became my thesis adviser. He was a very kind old man and he let me do anything in their lab I wanted to – but eventually I moved out of there because doing synthetic chemistry in a poorly equipped biology lab was difficult. I managed to re-synthesize some of their substances – the compounds turned out to be active in antiproliferative assay done at another institute but we could not really test them extensively anymore and my adviser retired and that was the end of the project.

It was an interesting experience. The sad part of it was that our colleague who actually started the work and made most contributions before retiring used to be a reputable virologist – he pioneered interferon production method using human fibroblast cultures. Later he got interested in analysing a ‘natural cancer cure’ from a quack that seemed to have positive results. So this virologist began looking for the active principle and was doing animal testing on the extracts – a legitimate research program – but his chemistry and also the animal work done in a very limited setting was not up to the task. The lab absolutely lacked the resources needed for natural product research and synthesis. He had nobody to test it so he brough mouse cages into the lab… He tried to push forward on non-existent budget and without the necessary expertise, simply by improvising and calling favors on his friends to gain the testing and instrument access unofficially. With this strange research project going on for years, his confrontational style also won him no admiration with the management and the neighboring groups at his institute. He was never forced to stop but he got increasingly isolated in his little lab.

He did succeed in finding something interesting – a class of naturally-occurring substances related to synthetic cytotoxic ether-phospholipid analogs of PAF (that were independently developed for chemotherapy). His natural ether phospholipids seemed to work on some cancer lines and were well-tolerated by normal fibroblasts. They also showed a promise in xenograft mice tumor models. Since these phospholipid substances are naturally-occuring in humans (under conditions like ischemia), the hope was that perhaps they could be less toxic than the synthetic alkylphospholipids.

As he and his few colleagues were getting increasingly anxious about the project progress and its lack of support, they decided to campaign in the media. They were also giving out their naturally-derived quack remedy to cancer patients; they genuinely thought they were doing favor to these patients… and they antagonised the medical community. That made them even more exasperated and resentful.

I had nothing to do with this patient compassionate “treatment”, I only re-synthesized some substances in a pure form and got them independently tested; the compounds were active in a cancer cell culture but their poor solubility was a major complication:

Here is the synthesis I did for the project – it turned out to be a fairly straightforward scheme although it took some effort to figure out. (There was a bit more to it; I was also isolating these substances from a natural phospholipid mixture and characterizing them by chemical derivatization).

This project story from 20 years ago shows that people promoting the “natural cancer remedies” may even have careful scientific approach at the beginnig but as they continue they get carried away by wishful thinking to the point of delusion. They start as researchers but derail as quacks. When you are working on biologically active natural substances and you have great hopes for the medicinal potential of your project you have to be very conservative about the way you interpret and present your results. You can’t skip the preclinical research stage even when your compounds are “natural and non-toxic”. You need to look for any artifact argument against your promising results – if there is a discrepancy in your numbers you have to understand it (could the results be possibly influenced by the purity/instability/solubility of your compounds, the way you make the stock solution, grow the cells or inject the mice?). Claiming that your critics from the medical community are hindering you because they surely are in confederacy with pharma companies is the surest method of earning yourself a crackpot reputation.

Also, please don’t take a thesis adviser who works on a fringe project even if you are excited about the research – after finishing my thesis; my adviser and his colleague could not help me with my career even though they were well meaning. They retired and our work came to nothing.

Like this:

It is very appropriate of you to mention the way things should be done. But looking from the old Prof’s perspective (that too 20 years back) with nonexistent funds makes me to worry for all such people. A nice perspective, and a nice post. Is your Ph.D from Prague? How do you comapre it to the one that is obatined form US (…say from a 4th tire US universuty)?

We all graduated at the time with a Mgr degree, after a 5-year program that included 2-3 years of thesis work so the degree is roughly equivalent MS. Then one would do a second thesis, another 2-3 years for RNDr = PhD.

After graduating the army wanted me to serve mandatory one year as a conscript so I got a lab assistant job at institute where I enroled into a PhD program. Before the program had started I run away to US, to work for a company – rather than living on a meagre stipend (and of my mom) for few more years and then serving in the army.

Things must have changed a great deal in Prague over the last two decades – and since I am not keeping touch with colleagues there (several good chemists that I knew from Prague are now working in US or UK) I really don’t know how to compare. Obviously, 20 years ago at the end of the commie era, the overall research quality was unimpressive but there were few remarkable exceptions also.

This was not a typical thesis project – it was very fringe even back then and there; I remember several people tried to talk me out of it.

It is important to be passionate about any goal worth achieving. Passion is a human emotion which may have either positive or negative consequences in one’s work. Scientific method and emotion often result in an immisable product. It is so unfortunate when one is remembered by works done at the end of a career rather than at its pinnacle.

I worked for a really poor young assistant professor for my final year project in my undergrad course, and it was really painful to beg, steal and/or borrow glassware everyday. We also had to synthesize intermediate molecules from scratch because he couldn’t afford to buy them for us. After one year of enduring such conditions, I swore that I would only work for the richest guy in the Dept and I left. LOL! Passion is important, but money sure helps – alot.

While working on this project I earned a reputation of appropriating any useful research item that was not bolted to the floor, things like glassware, tins with solvents, drums of silica… I remember climbing over the wall and then scaling a fence to get into yard of institute where I was no longer employed – they were storing their dry ice in chests on their yard. (I rode a public bus with backpack filled with the pilfered dry ice bricks – the fellow passengers on the bus watching my frosty and “smoking” backpack with horror…) I also got a loan to buy the unavailable chemicals from Aldrich and I finished re-paying it only after I got a job in US. It took lots of determination to continue on that project, and I changed my lab few times in the process.

Drums of silica? How did you pull that one off? What about cylinders of N2? It took two girls (me and a fellow student) to push a typical cylinder of N2 (taller than both of us!) back to the lab from the store. The store was at the foot of the hill, and our lab was at the top of the hill. When it rained, things usually get very dicey 🙂

I did not steal tanks with nitrogen and the dry ice heist happened only twice I think. 3 liter cans of purified solvents migrated from one institute that had its own solvent purification facility into other labs at our university – you just had to be reasonable (=not too greedy) and know people that could help you. I once carried a giant bottle for someone at my uni, of MTBE. The stopper was leaking, and it was on a late night bus – it was past midnight and I missed the last subway – and the comments of all the drunks on the bus when they noticed the minty reek of MTBE were hilarious. (“Some old lady with arthuitis put her ointments on” etc)

I think the passion (probably craziness) coupled with the poor research boss drives people nuts to venture in to those extra curricular activities to get the research done. Nevertheless, you learn a lot of chemistry as you will have to make the SMs from the scratch, and also your communication skills+people skills improve a lot. I am sure that MILKSHAKE would not have been this MILKSHAKE without those beatings he had to withstand. I can relate to his story in the sense that I used to enter in to the stock room of a rich guy that used to be on the top floor through the rear window. I used to fear that my death (incase of falling from there) would be pictured as a suicide because of the inability to complete the synthesis of some big toxin molecules that I was assigned where as I loved the hurdles involved. This is the case being in a rich lab from this country, so I could only assume the things with a boss that cannot afford.

milkshake I have done some “midnight appropriations” in my time but am a mere amateur and bow to your professional status. In grad school I would never wash my glassware at night because any clean stuff was likely to end up in someone’s hood before I could use myself. Your dry ice story is similar to my daughter’s experience in Boston T as she worked on a play that needed some dry ice for smoke machine which she picked up and transported in a small cooler. She indeed got many strange looks.

My two cents to people going to grad school: although do want a prof that has good equipment and money support it is more important that the projects and the personalities (prof and his group) are compatible with ones desires and own attitudes. You’ll be spending much time over several years and if don’t like what you do or who’s around can be very exasperating and wasteful. Unless you have direct insider ino pick a school that has several people in your area of interest so can learn once you get there.

tomn I have used the slurry/syringe method many times. I think was like a 20 or 50 mL plastic syringe and cut the nipple off a bit so sucked/flowed better. I trust you already know KH (when oil removed) is much more reactive/flammable than NaH so will not tolerate exposure to humid day.

Same goes to Dilutedmagnetic… I work for a stingy boss during my MSc years. Beg, borrow, pleaded… from glasswares to analytical balance. Something that I don’t want to go through again. But I must say Milkshake… you do have a very colourful history. Guess, it does make you stronger everyday. POWER!!!

On the other hand, someone stole our analytical balance! OMG! That was the only expensive thing in the lab. After that, we all had to go next door to use their balance. Good thing we had nice neighbours 🙂

When I was working in Australia (no offence to Australians), I used to watch stories on the news about bust-ups of illegal meth-labs, and drool at the equipment the cops were removing from the premises. BRAND NEW ROTAVAPS! BRAND NEW HEATING MANTLES! DECENT LOOKING HIGH VACUUM PUMPS! LOL! Such is life…

Completely random story, but in my chem department they lock up at night with the usual security tag-swipe doors. Apart from one serious oversight – the underground car park was blocked with a security arm (for cars) and was unmanned overnight. This was easily bypassed by a group of thieves one night , who from the car park simply called the goods elevator down and gained access to all levels. There were internal security doors of course, but they did not block access to three “isolated labs” used typically for particularly offensive chemistry such as work using thiols or cyanide. There the thieves apparently loaded trolleys with three rotary evaporators, balances, glassware and more. Although it was an oversight to leave these labs wide open to the public, knowing the location of the elevator and its unrestricted access to certain “toxic labs” probably couldn’t have been known without some inside information. The equipment was never recovered, so one would imagine that these balances and rotavaps are now supplying the city with meth or otherwise.